EASL2019 FRI-131 HBsAg水平对HBeAg细胞免疫应答的影响 慢性乙型肝

StephenW

FRI-131
Impact of HBsAg level on cellular immune responses in HBeAg
negative patients with chronic hepatitis B virus infection
Elmira Aliabadi1,2, Carola Mix1,2, Michael P. Manns1,2,3, Anke Kraft1,2,
Markus Cornberg1,2,3. 1Hannover Medical School, Department of
Gastroenterology, Hepatology and Endocrinology, 30625, Hannover,
Germany; 2German Centre for Infection Research (Deutsches Zentrum
für Infektionsforschung DZIF), Partner-site Hannover-Braunschweig,
30625, Hannover, Germany; 3Centre for Individualized Infection
Medicine (CIIM), c/o CRC Hannover, 30625, Hannover, Germany
Email: [email protected]
Background and aims: Worldwide 250 million people are persistently
infected with hepatitis B virus (HBV) leading to 686.000 deaths
annually. The level of hepatitis B surface antigen (HBsAg) produced
by HBV-infected hepatocytes could have an immunomodulatory role
in HBV infected patients. However, the correlation between HBsAg
level and HBV-specific T cell immune responses in patients with
chronic HBV (CHB) and HBeAg negative has not been well defined.We
investigated HBV-specific immune responses in HBeAg negative
patients with different levels of HBsAg during the natural course of
chronic hepatitis B.
Method: 44 HBeAg negative patients were categorized into 4 groups
based on their HBsAg level (HBsAg < 100 IU/ml, HBsAg 100–999 IU/
ml, HBsAg 1, 000-9, 999 IU/ml, HBsAg ≥ 10, 000 IU/ml). PBMCs were
isolated from these patients and different subsets of immune cells
were phenotypically characterized using 14 color flow cytometry.
Furthermore, IFNγ+ HBV-specific T cell responses were measured
after in vitro culture with overlapping peptides covering polymerase,
surface and core of HBV genotype D in the presence or absence of
anti-PD-L1 antibody.
Results: Patients with different levels of HBsAg showed similar
frequencies of memory, naïve and effector T cells, γδ T cells, Treg cells,
MAIT cells, B cells, NK cells, monocytes and DCs. Interestingly, the
frequency of γδ T cells, Treg cells and CD1c- myeloid DCs was
significantly increased in CHB patients compared to healthy
individuals.
Stimulation of PBMCs with HBV overlapping peptides induced core and
polymerase-specific T cell responses. However, surface-specific T
cell responses were hardly detectable. We observed a trend towards
higher HBV-specific T cells in patients with HBsAg < 100 IU/ml. In
patients with HBsAg ≥ 10, 000 IU/ml a high variability of T cell
responses were detected. Interestingly, in these patients stronger Tcell responses were associated with young age, female gender and
low HBV DNA. In general, CD4+ T cell response to in vitro stimulation
with HBV overlapping peptides was stronger than CD8+ T cell
responses. Blocking the PD-1/PD-L1 pathway during in vitro culture
significantly increased the core-specific T cell response in patients
with HBsAg < 100 IU/ml.
Conclusion: Our data suggests that HBsAg level per se may have only
a minor impact on the cellular immune responses. Patients with
HBsAg < 100 IU/ml, showed slightly stronger T cell responses to in
vitro HBV peptide stimulation especially after using checkpoint
inhibitors. Therefore, patients with low HBsAg levels may demonstrate
better responses to immune-modulatory treatment.

StephenW

FRI-131
HBsAg水平对HBeAg细胞免疫应答的影响
慢性乙型肝炎病毒感染的阴性患者
Elmira Aliabadi1,2，Carola Mix1,2，Michael P. Manns1,2,3，Anke Kraft1,2，
Markus Cornberg1,2,3。 1，汉诺威医学院
胃肠病学，肝脏病学和内分泌学，30625，汉诺威，
德国; 2德国感染研究中心（Deutsches Zentrum
fürInfektionsforschungDZIF），合作伙伴网站Hannover-Braunschweig，
30625，德国汉诺威; 3中心个体感染
医学（CIIM），c / o CRC汉诺威，30625，汉诺威，德国
电子邮件：[email protected]
背景和目标：全球有2.5亿人坚持不懈
感染乙型肝炎病毒（HBV）导致686.000人死亡
每年。乙肝表面抗原（HBsAg）的水平产生
由HBV感染的肝细胞可以具有免疫调节作用
在HBV感染的患者中。但是，HBsAg之间的相关性
患者的水平和HBV特异性T细胞免疫反应
慢性HBV（CHB）和HBeAg阴性尚未明确定义
研究了HBeAg阴性的HBV特异性免疫应答
HBsAg自然过程中不同程度的患者
慢性乙型肝炎
方法：将44例HBeAg阴性患者分为4组
根据他们的HBsAg水平（HBsAg <100 IU / ml，HBsAg 100-999 IU /
ml，HBsAg 1,000-9,999 IU / ml，HBsAg≥10,000IU/ ml）。 PBMC是
从这些患者和不同的免疫细胞亚群中分离出来
使用14色流式细胞仪对表型进行表征。
此外，测量IFNγ+ HBV特异性T细胞应答
用覆盖聚合酶的重叠肽进行体外培养后，
HBV基因型D的表面和核心是否存在
抗PD-L1抗体。
结果：不同HBsAg水平的患者表现相似
记忆频率，幼稚和效应T细胞，γδT细胞，Treg细胞，
MAIT细胞，B细胞，NK细胞，单核细胞和DC。有趣的是，
γδT细胞，Treg细胞和CD1c-髓样DC的频率为
与健康人相比，CHB患者显着增加
个人。
用HBV重叠肽诱导PBMC诱导核心和细胞凋亡
聚合酶特异性T细胞反应。但是，表面特异性T.
细胞反应几乎检测不到。我们观察到了一种趋势
HBsAg <100 IU / ml患者的HBV特异性T细胞较高。在
HBsAg≥10,000IU/ ml的患者T细胞变异性高
检测到反应。有趣的是，在这些患者中，较强的T细胞反应与年龄，女性和女性有关
低HBV DNA。一般来说，CD4 + T细胞对体外刺激的反应
与HBV重叠肽相比，CD8 + T细胞更强
响应。在体外培养期间阻断PD-1 / PD-L1途径
显着增加患者的核心特异性T细胞反应
HBsAg <100 IU / ml。
结论：我们的数据表明HBsAg水平本身可能只有
对细胞免疫反应的轻微影响。患者
HBsAg <100 IU / ml，显示出稍强的T细胞反应
体外HBV肽刺激尤其在使用检查点后
抑制剂。因此，HBsAg水平低的患者可能会表现出来
对免疫调节治疗有更好的反应。